While much work has explored the role of Immunoregulation in IBD, the genetics for this role In human is limited, their antigenic specificities of regulatory T cells are poorly understood, and strategies for their therapeutic manipulation are lacking. During the previous award period, studies in Project 3 uncovered a new immunoregulatory T cell population, termed invariant HLA-E T cells (Qa-1 in mice), with antigenic specificity for a prevalent antigenic complex (HLA-E/Hsp60.4 peptide) characteristic of target cells undergoing the molecular stress response. This Invariant T cell population Is dependent on commensal microbial composition, and cytolytically targets activated immune cell types yielding In vivo protection In animal IBD models. New collaborative work suggests that HLA-E alleles affect UC disease severity, and that certain inhibitory NK receptors/HLA binding partners (K1R2DL2/3 and HLA-C1) both modify CD risk, and affect invariant HLA-E T cell levels. This project tests two hypotheses: (a) patients with gene variants for loci controlling inhibitory NK receptor/HLA pairs, or for microbial serologies, will have reduced mucosal invariant T cells; and (b) patients with combinations of those gene variants will have more severe inflammation, and more severe clinical course. These hypotheses will be tested by determining (1) the tissue distribution and function of invariant HLA-E T cells; (2) the genetic effect of inhibitory NK receptor/MHCI and Qa-1 (the murine HLA-E homologue) on the efficiency and mechanism of Invariant Qa-1 T cell immunoregulation in mice; and (3) the genetic interaction of HLA-C1, K1R2DL2/3, HLA-E, NKG2A, and anti-microbial antibodies (levels and associated genetic loci) on Invariant HLA-E T cells and disease severity. If successful, these studies will reveal how genetic loci for two classes of receptors, and host traits in commensal microbial interaction, modulate a new class of regulatory T cells and their role In severity of disease in CD and UC. Such genetic traits to stratify patients for this mode of immunoregulation deficiency and its potential therapeutic Intervention.